Abstract Text: The microbiota of the oral cavity is composed of bacteria, fungi, viruses, archaea, and protozoa. Imbalances in the periodontal microbiota in a susceptible host and the proliferation of keystone pathogens are responsible for causing oral dysbiosis. When dysbiosis occurs, the subgingival periodontal bacteria trigger a chronic inflammatory process, destroying periodontal support tissues and systemic low-grade inflammation. This systemic can contribute to oral cancer development. Oral squamous cell carcinoma (OSSC) represents 95% of cancers in the oral cavity. Despite advances in diagnosis and treatment, OSCC is diagnosed late, starting with a pre-malignant lesion known as leukoplakia. Recently, periodontitis has been related to the development of chronic diseases. We evaluated oncogenic transformation in a cohort of patients with leukoplakia or OSCC the different signatures in long non-coding RNAs and the immunomodulatory molecules involved in malignant transformation, these studies were complemented with histopathology analysis. Also, we corroborate these markers in paraffin samples from secondary tumors to evaluate the metastatic niche. We obtained a difference in non-coding RNA signature samples from patients with leukoplakia and OSCC, which correlates with the different immunomodulatory molecules, and the histopathology studies in leukoplakia and OSCC. In addition, we determined the presence of keystone periodontal pathogens in the tissue samples of leukoplakia and OSCC and we study the small extracellular vehicles (EVs) from saliva to evaluate biomarkers for diagnosis of these pathologies. This study provides a new perspective on the OSCC since it includes new components to the view: the inflammatory effect of periopathogens, EVs, and the non-coding RNAs.